Sulpur derivatives containing a retroamide bond as inhibitors of endothelin-converting enzymes

ABSTRACT

The following products:  
     [S—R + , S + )] N-[1-(mercaptomethyl)-2-phenylethyl]-alpha-[[phenylmethoxy) carbonyl] amino]-1H-indole-3-propanamide,  
     2′-cyano-alpha-[[[1-mercaptomethyl)-2-phenylethyl] amino] carbonyl] (1,2′-biphenyl)-4-propanoic acid,  
     (R)N-(1-mercaptomethyl)-2-phenylethyl)-11-phenoxy-undecanamide,  
     said products being in all possible racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with pharmaceutically acceptable mineral and organic bases of said products of formula (I) having an inhibitory activity on enothelin-converting enzymes.

[0001] The present invention relates to new sulphur derivativescontaining a retroamide bond, their preparation process, the newintermediates obtained, their use as medicaments, the pharmaceuticalcompositions containing them and the new use of such derivatives.

[0002] A subject of the present invention is the products of formula(I):

[0003] in which:

[0004] R₁ represents an phenyl or biphenyl radical optionallysubstituted by one or more radicals chosen from halogen atoms, thefollowing radicals: optionally protected hydroxyl, linear or branchedalkoxy containing up to 4 carbon atoms, cyano, free, salified,esterified or amidified carboxy, benzyloxy and the dioxol radical,

[0005] n1 and n2, identical or different, represent the integer 0 or 1,

[0006] R₂ represents a hydrogen atom or a methyl radical substituted bya phenyl, phenylthio or indolyl radical and optionally by a secondphenyl radical, these phenyl, phenylthio and indolyl radicals beingoptionally substituted by one or more radicals chosen from halogen atomsand the following radicals; optionally protected hydroxyl, linear orbranched alkoxy containing up to 4 carbon atoms, cyano, free, salified,esterified or amidified carboxy, benzyloxy, thienyl, naphthyl andphenyl, these three last radicals being themselves optionallysubstituted by one or more radicals chosen from halogen atoms and thefollowing radicals: optionally protected hydroxyl, linear or branchedalkoxy containing up to 4 carbon atoms, cyano and free, salified,esterified or amidified carboxy,

[0007] A represents the free, salified, esterified or amidified carboxyradical free or salified tetrazolyl radical, or an alkyl radical,containing up to 10 carbon atoms and substituted by a radical chosenfrom the following radicals: free, salified, esterified or amidifiedcarboxy, the optionally protected hydroxyl, alkoxy containing up to 4carbon atoms, phenoxy, phenyl, naphthyl, thienyl, indolyl and pyridyl,these radicals being optionally substituted by one or more radicalschosen from halogen atoms and the following radicals: optionallyprotected hydroxyl, linear or branched alkoxy containing up to 4 carbonatoms, cyano and free, salified, esterified or amidified carboxy,

[0008] 1 and 2 indicating, if appropriate, the asymmetric centres of theproducts of formula (I),

[0009] said products of formula (I) being in all possible racemic,enantiomeric and diastereoisomeric isomer forms, as well as the additionsalts with mineral and organic acids or with the mineral and organicbases of said products of formula (I).

[0010] In the products of formula (I) and in what follows:

[0011] the term linear or branched alkyl radical designates thefollowing radicals: methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and alsoheptyl, octyl, nonyl and decyl as well as their linear or branchedposition isomers,

[0012] the term linear or branched alkoxy radical designates thefollowing radicals: methoxy, ethoxy, propoxy, isopropoxy, linear,secondary or tertiary butoxy, pentoxy or hexoxy as well as their linearor branched position isomers,

[0013] the term halogen atom preferably designates the chlorine atom,but can also represent a fluorine, bromine or iodine atom.

[0014] The hydroxyl radical can in particular be in the form of thetrifluoromethylsulphonyloxy radical.

[0015] The carboxy radical or radicals of the products of formula (I)can be salified or osterified by the various groups known to a personskilled in the art among which there can be mentioned, for example:

[0016] among the salification compounds, mineral bases such as, forexample, an equivalent of sodium, of potassium, of lithium, of calcium,of magnesium or of ammonium or organic bases such as, for example,methylamine, propylamine, trimethylamine, diethylamine, triethylamine,N,N-dimethylethanolamine, tris (hydroxymethyl) amino methane,ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine,benzylamine, procaine, lysine, arginine, histidine, N-methyl-glucamine.

[0017] The sodium or potassium salts are preferred,

[0018] among the esterification compounds, the alkyl radical in order toform alkoxy carbonyl or arylalkoxycarbonyl groups, such as, for example,methoxycarbonyl, ethoxycarbonyl, n-propoxy- and isopropoxy-carbonyl,n-butoxy-, isobutoxy- and tert-butoxy-carbonyl or benzyloxycarbonyl,these alkyl radicals can he substituted by radicals chosen for examplefrom halogen atoms, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino oraryl radicals such as, for example, in the chloromethyl, hydroxypropyl,methoxymethyl, propionyloxy-methyl, methylthiomethyl,dimethylaminoethyl, benzyl or phenethyl groups.

[0019] There can also be mentioned the radicals formed with theremainders of easily cleavable esters such as the methoxymethyl,ethoxymethyl radicals; the acyloxyalkyl radicals such aspivaloyloxymethyl, pivaloyloxyethyl, acetoxymethyl or acetoxyethyl; thealkyloxycarbonyloxy alkyl radicals such as methoxycarbonyloxy methyl orethyl radicals, the isopropyloxycarbonyloxy methyl or ethyl radicals.

[0020] A list of such ester radicals can be found for example in theEuropean Patent EP 0 034 536.

[0021] By acidified carboxy is meant the groups of —CON(R₆) (R₇) type inwhich the identical or different R₆ and R₇ radicals represent a hydrogenatom or an alkyl radical having from 1 to 4 carbon atoms such as themethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl ortert-butyl radicals.

[0022] Among the —CON(R₆) (R₇) groups defined above, those in which the—N(R₆) (R₇) radical represents the amino, mono or dimethylamino radicalare preferred.

[0023] The N(R₆) (R₇) radical can also represent a heterocycle which mayor may not contain an additional heteroatom. There can be mentioned thepyrrolyl, imidazolyl, indolyl, piperidino, morpholino, piperazinylradicals. The piperidino or morpholino radicals are preferred.

[0024] Examples of the protective group of the protected hydroxylradical are given in particular in the usual book known to a personskilled in the art: Protective Groups in Organic Synthesis, Theodora W.Greene, Harvard University, printed in 1981 by Wiley-IntersciencePublishers, John Wiley & sons.

[0025] The addition salts with mineral or organic acids of the productsof formula (I) can be, for example, the salts formed with the followingacids: hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric,phosphoric, propionic, acetic, formic, benzoic, malaic, fumaric,succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic,alkylmonosulphonic acids such as for example methanesulphonic acid,ethanesulphonic acid, propanesulphonic acid, alkyldisulphonic acids suchas for example methanedisulphonic acid, alpha, beta-ethanedisulphonicacid, arylmonosulphonic acids such as benzenesulphonic acid andaryldisulphonic acids.

[0026] More particularly there can be mentioned the salts formed withhydrochloric or methanesulphonic acids for example.

[0027] It should be remembered that the stereoisomerism can be definedin its widest sense as the isomerism of compounds having the samestructural formulae, but the different groups of which are arrangeddifferently in space.

[0028] It is understood that the definition of the products of formula(I) as defined above includes all possible stereoisomers, all racemicmodifications, all optical isomers and all mixtures of these productswhich would have the activity indicated hereaftcr.

[0029] The products of formula (I) contain in particular two centres{circle over (1)} and {circle over (2)}, {circle over (1)} beingasymmetrical and {circle over (2)} being asymmetrical when R₂ does notrepresent a hydrogen atom. A particular subject of the present inventionis the products of formula (I) in which the first asymmetrical centre{circle over (1)} is preferably in R form, the second centre {circleover (2)} can preferably be in racemic or enantiomeric R or S form.

[0030] A particular subject of the present invention is the products offormula (I) as defined above, in which R₁, R₂, and n2 have the meaningsindicated above,

[0031] n1 represents the integer 1,

[0032] and A represent the free, salified, esterified ou amidifiedcarboxy radical or an alkyl radical, containing at most 10 carbon atomsand substituted by a radical chosen from the free, salified, esterifiedou amidified carboxy radicals, optionally protected hydroxyl radicals,alkoxy radicals containing at most 4 carbon atoms, and the phenoxyradical, said products or formula (I) being in all possible racemic,enantiomeric and diastereoisomeric isomer forms, as well as the additionsalts with mineral and organic acids or with mineral and organic basesof said products of formula (I).

[0033] A more particular subject of the present invention is theproducts de formula (I) as defined above, in which R₁ represents aphenyl or biphenyl radical, optionally substituted by a halogen atom, orby a hydroxyl radical optionally in the form of of thetrifluoromethyl-sulphonyloxy radical,

[0034] n1 represents the integer 1,

[0035] n2 represents the integer 0,

[0036] R₂ represents a hydrogen atom or a methyl radical substituted bya plenyl radical, itself optionally substituted by a thienyl or phenylradical itself optionally substituted by a cyano radical,

[0037] A represents the tree, salified, esterified ou amidified carboxyradical or an alkyl radical, containing at most 10 carbon atomssubstituted by a phenoxy radical, said products of formula (I) being inall possible racemic, anantiomeric and diastereoisomeric isomer forms,as well as the addition salts with mineral and organic bases of saidproducts of formula (I).

[0038] In particular, R₁ can represent a phenyl or biphenyl radical,optionally substituted by a bromine atom.

[0039] A quite particular subject of the present invention is theproducts de formula (I) as defined above, the names of which follow:

[0040] [S—(R^(*),S^(*))] N-[1-(mercaptomethyl) 2phenylethyl]-alpha-[[(phenylmethoxy) carbonyl]amino]-1H-indole-3-propanamide,

[0041] 2′-cyano-alpha-[[[1-(mercaptomethyl)-2-phenylethyl] amino]carbonyl] (1,1′-biphenyl)-4-propanoic acid,

[0042] (R)N-(1-mercaptomethyl)-2-phenylethyl)-11-phenoxy-undecan-amide,

[0043] said products of formula (I) being in all possible racemic,enantiomeric and diastereoisomeric isomer forms, as well as the additionsalts with mineral and organic bases of said products of formula (I).

[0044] A subject of the present invention is also the preparationprocess for the products of formula (I), such as defined above,characterized in that a product of formula (II):

[0045] in which n1 has the meaning indicated above and R′₁, has themeaning indicated above for R₁ in which the optional reactive functionsare optionally protected, is subjected either to the action of acompound of formula (III):

[0046] in which R′₂ has the meaning indicated above for R₂ in which theoptional reactive functions are optionally protected, and R representsan alkyl or arylalkyl radical, in order to obtain the product of formula(IV):

[0047] in which n1, R′₁, R′₂ and the meanings indicated above, or to theaction of an acid halide of formula (V):

[0048] in which n2 has the meaning indicated above, HaI represents ahalogen atom, R′₂ has the meaning indicated above and A′ has the meaningindicated above for A in which the optional reactive functions areoptionally protected, such as in particular A′ does not represent a freecarboxy radical, in order to obtain a product of formula (VI):

[0049] in which n1, n2, R′₁, R′₂ and A′ have the meanings indicatedabove,

[0050] which products of formula (IV) and (VI), in order to obtainproducts of formula (I) or to convert the products of formula (I) intoother products of formula (I), can be treated, if desired and ifnecessary, to one or more of the following reactions, in any order:

[0051] a saponification reaction of the ester function into an acidfunction,

[0052] a conversion reaction of the cyano function or amide functioninto an acid or tetrazolyl function,

[0053] a conversion reaction of the alkoxy function into the hydroxylfunction,

[0054] an esterification, salification or amidification reaction of theacid function,

[0055] a reaction which releases the thiol function from the radical

[0056] an elimination reaction of the protective groups which can becarried by the protected reactive functions,

[0057] a salification reaction by a mineral or organic acid or base inorder to obtain the corresponding salt,

[0058] said products of formula (I) thus obtained being in all possibleracemic, enantiomeric and diastereoisomeric isomer forms.

[0059] Under the preferred conditions for implementing the invention,the process described above can be carried out in the following fashion:

[0060] the reaction of the product of formula (I) as defined above withthe product of formula (III) as defined above is preferably carried outwith a coupling agent such as for example EDC in methylene chloride oralso BOP methyl cyanide in the presence of triethylamine, or also DDC,

[0061] the reaction of the product of formula (II) as defined above withthe product of formula (V) as defined above is preferably carried out,in methylene chloride in the presence of pyridine. In the compound offormula (V), the halogen atom is preferably a chlorine atom.

[0062] According to the values of R′₁, R′₂ and A′, the products offormulae (IV) and (VI) constitute or do not constitute products offormula (I) and can produce products of formula (I), or be convertedinto other products of formula (I) by being subjected to one or more ofthe reactions indicated above which can be carried out, for example, asindicated hereafter.

[0063] The various reactive functions which can be carried by certaincompounds of the reactions defined above can, if necessary, be protected: it is for example the hydroxyl or free carboxy radicals which can beprotected by the appropriate protective groups.

[0064] The following non-exhaustive list, of examples of the protectionof reactive functions can be mentioned:

[0065] the amine groups can be protected in the form of othercarbamates, such as those known in the chemistry of peptides,

[0066] the hydroxyl groups can be protected for example by alkylradicals such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl,methoxymethyl, tetrahydropyrannyl, benzyl or acetyl.

[0067] The products described above can, if desired, be the object, onthe optional carboxy functions, or esterification, salification oramidification reactions, which can be carried out according the usualmethods known to a person skilled in the art.

[0068] The acid functions of the products described above can be, ifdesired, amidified by a primary or secondary amine for example inmethylene chloride in the presence of, for example, 1-ethyl-3-(dimethylaminopropyl) carbodiimide hydrochloride at ambient temperature.

[0069] The acid functions acid can be protected for example in the formof esters formed with easily cleavable esters such as benzylic or thebutylic esters or esters known in the chemistry of the peptides.

[0070] The optional saponification reactions of the ester function intoan acid function of the products described above can, it desired, becarried out under the usual conditions known to a person skilled in theart in particular by acid or alkaline hydrolysis for example with sodaor potash in alcoholic medium such as, for example, in methanol or alsowith hydrochloric or sulphuric acid.

[0071] The optional cyano functions of the products described above can,if desired, be converted into an acid function under the usualconditions known to a person skilled in the art for example by a doublehydrolysis carried out in acid medium such as for example in a sulphuricacid, glacial acetic acid and water mixture, these three compoundspreferably being in equal proportions, or also in a soda, ethanol andwater mixture under reflux.

[0072] The optional cyano functions of the products described above can,if desired, be converted into the tetrazolyl function under the usualconditions known to a person skilled in the art such as for example bythe cycloaddition of a metal azide such as for example sodium azide ortrialkyltin azide on the nitrile function as indicated in the methoddescribed in the article referenced as follows:

[0073] J. Organometallic Chemistry., 33, 337 (1971) KOZIMA S.and al.

[0074] The acid functions can be converted into tetrazole as indicatedin the publication Bio. Med. Chem. Leh. 1995, 145.

[0075] The optional alkoxy functions such as in particular methoxy ofthe products described above can, if desired, be converted into thehydroxyl function under the usual conditions known to a person skilledin the art for example with boron tribromide in a solvent such as forexample methylene chloride, with pyridine hydrobromide or hydrochlorideor also with hydrobromic or hydrochloric acid in water ortrifluoroacetic acid under reflux.

[0076] The optional hydroxyl functions of the products described abovecan, if desired, be converted into an acid function by oxidation underthe usual conditions known to a person skilled in the art in theconditions such as for example by the action of Jones reagent to accessthe acids.

[0077] The elimination of the protective groups such as for examplethose indicated above can be carried out under the usual conditionsknown to a person skilled in the art in particular by an acid hydrolysiscarried out with an acid such as hydrochloric, benzene sulphonic orparatoluene sulphonic, formic or trifluoroacetic acid or also bycatalytic hydrogenation.

[0078] The phthalimido group can he eliminated with hydrazine.

[0079] A list of the different protective groups that can be used willbe found for example in the Patent BF 2 499 995.

[0080] The products described above can, if desired, be the object ofsalification reactions for example with a mineral or organic acid orwith a mineral or organic base according to the usual methods known to aperson skilled in the art.

[0081] The optional optically active forms of the products describedabove can be prepared by resolution of the racemics according to theusual methods known to a person skilled in the art.

[0082] Illustrations of such reactions defined above are given in thepreparation of the examples described hereafter.

[0083] The structures and properties of endothelin and of its precursorBig Endothelin are described in the literature such as for example inthe document WO 93/11154.

[0084] The products of formula (I) of the present invention have beenfound to have an inhibitory activity on the enothelin-converting enzymewhich allows the properly so-called endothelin to be obtained from BigEndothelin, which is thus an extremely powerful vasoconstrictor agent.

[0085] The products of formula (I) of the present invention cantherefore be used in the treatment of illnesses resulting fromabnormally high quantities of endothelin.

[0086] The compounds of formula (I) as defined above as well as theiraddition salts as defined above have useful pharmacological properties.

[0087] The products of formula (I) as defined above, endowed withinhibitory properties of the endothelin-converting enzyme, can thus inparticular reduce the quantities and therefore the effects ofendothelin, in particular the vasoconstrictor and hypertensor effectsinduced by endothelin. In particular an antiischemic effect is noted.

[0088] The products or formula (I) therefore also have the effect ofreducing the stimulating effects or endothelin at the level of all celltypes, in particular the smooth muscle cells, the fibroblasts, theneuronal cells and the bone cells.

[0089] These properties justify their use in therapeutics and aparticular subject of the invention is as medicaments, the products offormula (I),

[0090] said products of formula (I) being in all possible racemic,enantiomeric and diastereoisomeric isomer forms, as well as the additionsalts with pharmaceutically acceptable mineral and organic acids or withpharmaceutically acceptable mineral and organic bases of said productsof formula (I).

[0091] More particularly a subject of the invention is also, asmedicaments, the preferred products as defined by formula (I) above inwhich

[0092] R₁ represents a phenyl or biphenyl radical, optionallysubstituted by halogen atom,

[0093] n1 represents the integer 1,

[0094] n2 represents the integer 0,

[0095] R₂ represents a hydrogen atom or a methyl radical substituted bya phenyl radical, itself optionally substituted by a thienyl or phenylradical itself optionally substituted by a cyano radical,

[0096] A represents the free, salified, esterified or amidified carboxyradical or an alkyl radical, containing at most 10 carbon atomssubstituted by a phenoxy radical,

[0097] said products of formula (I) being in all possible racemic, oroptically active isomer forms, as well as the addition salts withpharmaceutically acceptable mineral and organic acids or withpharmaceutically acceptable mineral and organic bases of said productsof formula (I).

[0098] A quite particular subject of the invention is, as medicaments,the products described hereafter in the examples and in particular theproducts of formula (I) as defined above, the names of which follow:

[0099] [(S—(R^(*),S^(*))] N-[1-(mercaptomethyl)-2-phenylethyl]-alpha[[(phenylmethoxy) carbonyl] amino]-1H-indole-3-propanamide,

[0100] 2′-cyano-alpha-[[[1-(mercaptomethyl)-2-phenylethyl]amino]carbonyl] (1,1-biphenyl)-4-propanoic acid,

[0101] (R)N-(1-mercaptomethyl)-2-phenylethyl)-11-phenoxy-undecan-amide,

[0102] as well as the addition salts with pharmaceutically acceptablemineral and organic bases of said products of formula (I).

[0103] The medicaments, which are a subject of the invention, thereforefind their use in the treatment, by use of an inhibitory agent of theendothelin-converting enzyme, for illnesses such as, for example,vascular spasms, vasospasm as a result of a cerebral haemorrhage,coronary spasms, peripheral vascular spasms as well as renalinsufficiencies. These medicaments can also be used in the treatment ofmyocardial infarction, of congestive cardiac insufficiency, in theprevention of post-angioplasty recurrence of stenosis, of cardiac andvascular fibrosis, in the treatment of atherosclerosis, of certain formsof hypertension such as in particular pulmonary hypertension, as well asin the treatment of asthma.

[0104] The medicaments, which are a subject of the invention, can alsofind a use in the treatment of osteoporosis, prostatic hypertrophia andas neuronal protectors.

[0105] The invention extends to the pharmaceutical compositionscontaining as active ingredient at least one of the medicaments asdefined above.

[0106] These pharmaceutical compositions can be administered by buccal,rectal route, by parenteral route or by local route as a topicalapplication on the skin and mucous membranes or by injection byintravenous or intramuscular route.

[0107] These compositions can be solid or liquid and be presented in allthe pharmaceutical forms commonly used in human medicine, such as forexample, plain or sugar-coated tablets, capsules, granules ,suppositories, injectable preparations, ointments, creams, gels andaerosol preparations; they are prepared according to the usual methods.The active ingredient can be incorporated with excipients usuallyemployed in these pharmaceutical compositions, such as talc, gum arabic,lactose, starch, magnesium stearate, cocoa butter, aqueous ornon-aqueous vehicles, fatty substances of animal or vegetable origin,paraffin derivatives, glycols, various wetting, dispersing oremulsifying agents, preservatives.

[0108] The usual dose, variable according the product used, the patienttreated and the illness in question, can be, for example, from 1 to 300mg per day in an adult, by oral route or from 1 to 100 mg per day byintravenous route.

[0109] Certain starting products of formula (II), (III) and (V) areknown, may he commercially available or prepared according to the usualmethods known to a person skilled In the art or also for example asindicated in the European Patent EP 046569.

[0110] In particular certain products of formula (II) can also beprepared from other products of formula (II) for example by subjectingthem to one or more of the reactions described above, carried out underthe conditions also described above.

[0111] Preparations for the compounds of formula (II) are indicated inthe examples described hereafter.

[0112] It should be noted that the compound of formula (II) can be inracemic or optically pure form and that, consequently, the product offormula (IV) obtained can also be in racemic or optically pure form.

[0113] The compound of formula (II) in which n1 represents the integer 1and R′: represents the phenyl radical can be prepared as indicated inPreparation 1E of EP 0465369,

[0114] either starting with the amino acid L-phenylalamine in order toproduce the product of formula (II) of form S,

[0115] or starting with the amino acid D-phenylalamine in order toproduce the product of formula (II) of form R,

[0116] or starting with a mixture of amino acids, L- and D-phenylalaminein order to produce the product of formula (II) of racemic form: thesecompounds of formula (II) thus obtained produce respectively, afterreaction with the compound of formula (III), a product of formula (IV)which will be respectively in {circle over (1)} in S form (Example 1),in R form Example 2) or in racemic form (Example 5).

[0117] Other compounds of formula (II), can be obtained in the samefashion starting from other amino acids.

[0118] In particular, the products of formula (II) in which R′₁,represents the biphenyl radical can he obtained starting from tyrosine.

[0119] Such a reaction is indicated in the preparation of Example 7,described hereafter.

[0120] Other compounds of formula (II), in which n1 represents theinteger 0 can be prepared starting from the corresponding acid in orderto produce by a Curtius reaction described in the literature, the soughtamine.

[0121] The compounds of formula (III) represent amino acids which can besubstituted on the nitrogen: such compounds of formula (III) may becommercially available or be prepared according to the usual methodsknown to a person skilled in the art.

[0122] The compounds of formula (V) are preferably acid chloridesprepared from the corresponding acid itself commercially available orprepared according to the usual methods known to a person skilled in theart, such as by condensation or an alkyl halide on a malonate.

[0123] Finally, a subject of the present invention is, as new industrialproducts, the compounds of formulae (IV) and (VI) as defined above.

[0124] Particularly a subject of the present invention is the use of theproducts of formula (I) as defined above, for the preparation of aninhibitory agent of the endothelin-converting enzyme.

[0125] Therefore a particular subject of the present invention is theuse of the products of formula (I) as defined above, for the preparationpharmaceutical compositions intended for the treatment, by inhibition ofthe endothelin-converting enzyme, for illnesses such as, in particular,hypertension induced by endothelin, vascular spasms, the effects of acerebral haemorrhage, renal insufficiencies, myocardial intarction ,cardiac insufficiency as well as the prevention of post-angioplastyrecurrence of stenosis and cardiac and vascular fibrosis.

[0126] The following examples illustrate the invention without howeverlimiting it.

EXAMPLE 1 [S—N-(1-mercaptomethyl)-2-phenylethyl)-2-((Phenylmethoxy)carbonyl) amino)-indole-3-propanamide

[0127] STAGE 1: [S—(R^(*),R^(*))] N-[1-[(acetylthio)methyl]-2-phenyl-ethyl)-alpha-[[(phenylmethoxy) carbonyl]amino]-1H-indole-3-propanamide

[0128] 103 mg of 1-(3-dimethylamino propyl) 3-ethyl carbodiimidehydrochloride in introduced into 10 ml of methylene chloride and 120 μlof triethylamine is added. Agitation is carried out for 10 minutes atambient temperature and 300 mg of N-carbobenzyloxy Triptomane (NCBz Trp)is added. The reaction medium is again left for 10 minutes at ambienttemperature then in one go 200 mg of the amino hydrochloride in S formis added, prepared as indicated in Preparation 1E of EP 0465369 withL-phenylalamine as starting product. The reaction is agitated for 4hours at ambient temperature, followed by evaporating, taking up in 30ml of ethyl acetate and washing twice with 0.1N hydrochloric acid, thenwith salt water (twice). After chromatography on silica with ethylacetate-hexane : 50-50 as eluant, 270 mg of expected product isobtained.

[0129] STAGE 2 :[S—N-(1-mercaptomethyl)-2-phenylethyl)-2-(((phenyl-methoxy) carbonyl)amino)-indole-3-propanamide

[0130] 120 mg of product obtained in Stage 1 above is introduced into 3ml of methanol. Then 0.34 ml of 1N soda is added and the reaction mediumis left for 1 hour at 0° C. After taking up in 4 ml of water,acidification is carried out with 1N hydrochloric acid until a pHapprox.=½ and the precipitate formed is filtered off. After drying, 120mg of expected product is obtained. M.p.−164° C. Rotatory power α_(D) aconcentration of 0.5 in methanol=−20.8°.

[0131] ANALYSES IR (CHCl₃) cm⁻¹ ═C—NH 3477 − 3420 >═O 1716 − 1673 SH2570 Aromatic C═C 1620 − 1578 − 1585 − 1497

[0132] Amide II

[0133] NMR (250 MHz 1H, CDCl3)

[0134] 0.81 (t, 1H, SH); 2.09 to 2.37 (m, CHCH ₂—SH)−2.64 (d, 2H, CH₂);3.11 (dd, 1H, CH ₂); 3.32 (dd, 1H); 4.20 (m 1H); 4.45 (n, 1H); 5.12 (s,2H, O—CH₂— ph); 5.43 (d, 1H, NH); 5.75 (d, 1, NH); 6.96 to 7.66 (n,14H); 8.07 (ws, 1H, indolc NH).

EXAMPLE 2[(R_(*),S_(*))]-N-[1-(mercaptomethyl)-2-phenylethyl]-alpha-[[(phenylmethoxy)carbonyl) amino)-1H-indole-3-propana-mide

[0135] The operation is carried out as in Example 1 using in Stage 1 theamine hydrochloride in R form prepared as indicated in Preparation IE ofEP 0465369 with as starting product D-phenylalamine. In this way 120 mgof expected product is obtained.

[0136] Rotatory power α_(D) at a concentration of 0.7.5 inchloroform=+8.5°

[0137] ANALYSES

[0138] NMR (1H, CDCl₃, 250 MHz, δ ppm)

[0139] 1.04 (t, 1H, SH); 2.3 to 2.7 (m, 4H, 2×CH₂); 3.11 (dd, 1H); 3.34(dd, 1H); 4.18 (m, 1H, CH—CH₂); 4.44 (m, 1H, CH—NHCHO); 5.11 (s, 2H, CH₂ ph); 5.40 (d, 1H, NH); 5.75 (d, 1H, NII); 8.02 (s, 1H, indole NH);6.95 (n, 3H, aromatic H); 7.10 to 7.4 (n, 11H, aromatics H′s); 7.66 (wd,1H, aromatics).

EXAMPLE 3 [S—(R^(*),R^(*))]-2-(((1,1-dimethylethoxy) carbonyl)amino-N-(1-(mercaptomethyl)-2-phenylethyl)-indole-3-propanamide

[0140] STAGE 1 : [S—(R^(*),R^(*))]-N-[1-[(acetylthio)methyl]-2-phenyl-ethyl ]-alpha-[[(1,1-dimethylethoxy) carbonyl]aminol]-1H-indole-3-propanamide

[0141] The operation is carried out as in Stage 1 of Example 1 usingN-BOC-tryptophan (N-terbutyloxycarbonyl-Trp) instead of N-CBZ-tryptophan(N-carbobenzyloxy-Trp). In this way 270 mg of expected product isobtained.

[0142] STAGE 2 : (S—(R^(*),R^(*))]-2-(((1,1-dimethylethoxy) carbonyl)amino)-N-(1-(mercaptomethyl)-2-phenylethyl)- indole-3-propanamide

[0143] The operation is carried out as in Stage 2 of Example 1 and inthis way 120mg or expected product is obtained. M.p.=77° C.

[0144] Rotatory power α_(D) at a concentration of 0.5 in methanol=−22.4°

[0145] ANALYSES

[0146] NMR (1H, CDCl₃, 250 MHz, δ ppm)

[0147] 0.87 (t, 1H, SH); 1.44 (s, 9H, tbu); 2.26 (m, CH₂, 2H); 2.65 (m,2H, CH₂-ph); 3.10 (dd, 1H, CH₂); 3.30 (dd, 1H, CH₂): 4.22 (m, 1, 1H,CH); 4.39 (m, CH, 1H); 5.13 (d, 1H, NH); 5.81 (d, 1H, NH); 6.99 (a, 1H,H₂ indole); 7 to 7.22 (m, 7H); 7.36 (d, 1H, Ar); 7.67 (s, 1H, Ar); 8.04(ws, 1H, NH indole).

[0148]IR (CHCl₃) cm⁻¹ ═C—NH 3477 − 3420 >═O 1706 − 1672 SH 2570Conjugated syst. Amide II 1620 − 1605 − 1513 − 1496 − 1490 Aromatic Meof tBu 1368

EXAMPLE 4 2′-cyano-alpha-[[[1-mercaptomethyl)-2-phenylethyl] amino]carbonyl]-(1,1′-biphenyl)-4-propanoic acid

[0149] STAGE 1 :2′-cyano-alpha-(ethoxycarbonyl)-(1,1′-biphenyl)-4-propanoyl chloride

[0150] 105 mg of sodium hydride at 60% in oil, washed twice beforehandwith pentane, is introduced into 15 ml or tetrahydrofuran and placed at0° C. under argon. A solution of 0.5 ml of terbutyl ethyl malonate isadded dropwise to 1 ml of tetrahydrofuran and the whole is left for 30minutes at ambient temperature then returned to 0° C. and a solution of410 mg of 4′-(bromomethyl)-(1,1′-biphenyl)-2-carbonitrile prepared asindicated in EP 0465369 (Example 49) is added dropwise. The solution isagitated for 1 hour at 0° C. and for 3 hours at ambient temperature,then acidified with 1N hydrochloric acid to a pH˜2. Then extraction iscarried out with ethyl acetate followed by drying. After chromatographyon silica with ethyl acetate-cyclohexane : 25-75 as eluant, 400 mg of anoil is obtained which is taken up in 10 ml of methylene chloride. 10 mlof trifluoroacetic acid is added and the whole is left for 3 hours atambient temperature then evaporation is carried out. The oily residue istaken up in 10 ml of thionyl chloride and left under agitationovernight. After evaporation of the thionyl chloride, the expected acidchloride is obtained used as it is in the following stage.

[0151] STAGE 2 : ethyl [R—(R^(*),R^(*))] and [R—(R^(*),S^(*))]alpha-[[[1-[(acetylthio) methyl]-2-phenylethyl] amino]carbonyl]-2′-cyano-(1,1′-biphenyl) 4 propanoate

[0152] 10 ml of methylene chloride is added to the product obtained inStage 1 above and, after having taken the reaction medium to reflux, 377mg of the amine hydrochloride obtained in Preparation 1E of EP 0465369is added. Then a few drops of pyridine is added in order to obtain apH˜4-6 and agitation is carried out under reflux for 4 hours. Thesolution is then evaporated and after chromatography on silica withethyl acetate-cyclohexane-methylene chloride : 25-25-50 as eluant, 400mg of expected product is obtained.

[0153] Analyses

[0154] NMR (1H, CDCl₃, 200 MHz)

[0155] 1.2 (2t, 3H, CH₃); 2.4 and 2.45 (2s, 3H, SAc); 2.7-3.5 (m, 7H);4.2 (m, 2H, CO₂CH₂); 4.4 (m, 1H, OC—CH—CO); 6.55 and 6.65 (2d, 1H, NH);7.1 to 7.6 (m, 11H); 7.7 (d, 1H, Ar); 7.9 (d, 1H, Ar).

[0156] STAGE 3 :2′-cyano-alpha-[[[1-(mercaptomethyl)-2-phenylethyl]amino]carbonyl]-(1,1′-biphenyl)-4-propanoic acid

[0157] 400 mg of product obtained in Stage 2 above is introduced into 5ml of tetrahydrofuran and 2.5 ml of water is added. Then 115 mg oflithium hydroxide is added at ambient temperature and the whole is leftunder agitation for 2 hours.

[0158] The reaction is then acidified by the addition of 1N hydrochloricacid to pH ˜2, then, after the addition of 5 ml of H₂O, extraction iscarried out three times with methylene chloride+10% of methanol.

[0159] After drying and evaporation, chromatography is carried out onsilica with methylene chloride-methanol : 90-10 as eluant and 280 mg ofexpected product (white foam) is obtained in the form of a mixture of 2diastereoisomers.

[0160] Tgum˜130° C.

[0161] Analyses

[0162] NMR (DMSO, 300 MRz, δ ppm)

[0163] 1.98 (m, SH); 2.4 to 3.3 (m, 7H); 3.93 and 4.02 (m, 1H,OC—CH—CO); 7.08 to 7.32 (m, 7H, Ar); 7.41 (m, 2H, Ar); 7.55 (m, 2H, Ar);7.77 (m, 1H), 7.92 (d, 1H, Ar); 8.32 and 8.38 (wd, 1H, CONH).

EXAMPLE 5 (S) alpha-(((1-(mercaptomethyl)-2-phenylethyl) amino)carbonyl) benzenepropanoic acid

[0164] STAGE 1 : alpha-(ethoxycarbonyl)-tenzenepropanoyl chloride

[0165] The operation is carried out as in Stage 1 of Example 4 usingbenzyl bromide (commercial) instead of 4′-(bromo-methyl) (1,1′-biphenyl)2-carbonitrile and in this way the expected product is obtained.

[0166] STAGE 2 : ethyl (S—(R^(*),S^(*))] and [S—(R^(*),S^(*))]alpha-[[[1-[(acetylthio) methyl]-2-phenylethyl] amino]carbonyl]-benzenepropanoate

[0167] The operation is carried out as in Stage 2 of Example 4 and inthis way the expected product is obtained.

[0168] STAGE 3 : (S) alpha-(((1-(mercaptomethyl) 2-phenylethyl) amino)carbonyl) benzenepropanoic acid

[0169] The operation is carried out as in Stage 3 of Example 4 and inthis way the expected product is obtained.

[0170] M.p.=65-70° C.;

[0171] Analyses :

[0172] NMR (DMSO, 300 MHz, δ ppm)

[0173] Mixture of 2 diastereoisomers (S,R) and (S,S)

[0174] 1.75 and 2.22 (wt, SF); 2.3 to 4.5 (m, 8H); 7 to 7.30 (m, 1OH);8.09 and 8.56 (d, 1H, CONH); 12.52 (wide m, COOH).

EXAMPLE 6 (R)N-(1-mercaptomethyl)-2-phenylethyl)-11-phenoxy-undecanamide

[0175] STAGE 1 : 11 phenoxy-undecanoyl chloride

[0176] 250 mg of 11-phenoxy undecanoic acid (commercial) is mixed with 2ml of pure thionyl chloride and the whole is left overnight at ambienttemperature. In this way 265 mg of expected product is obtained.

[0177] STAGE 2 : (R) N-[1-[(acetylthio)methyl]-2-phenylethyl]-11-phenoxy-undecanamide

[0178] The operation is carried out as in Stage 2 of Example 4 startingwith 265 mg of the product obtained in Stage 1 above and 120 mg of theamine hydrochloride (R form) obtained in Preparation IE of EP 0465369.In this way 150 mg of expected product is obtained.

[0179] STAGE 3 : N-(1-mercaptomethyl)-2-phenylethyl)11-phenoxy-undecanamide

[0180] 100 mg of the product obtained in Stage 2 above is introducedinto 4 ml of methanol and 120 μl of 2N soda is added at 0° C. The wholeis agitated for 1 hour at 0° C. Then 10 ml of water is added, the whiteprecipitate which forms is filtered out and dried. In this way 70 mg ofexpected product is obtained. M.p.=65° C.

[0181] NMR (CDCl₃, 300 MHz, δ ppm)

[0182] 1.20 to 1.02 (m, 17H); 2.14 (t, COCH₂); 2.66 (m, AR/sys resolved,CH,CH ₂SH) ; 2.88 (m, ph-CH ₂, CH); 3.95 (t, CH₃—CH₂-OPh); 4.37 (m,CH₂—CH(NII)CH₂); 5.55 (d, NHCO); 6.85 to 6.97 (m, 2H); 7.16 to 7.35 (m,OH).

EXAMPLE 7 2′-cyano-alpha-[[[3-(mercaptomethyl) 2-biphenylethyl] amino]carbonyl]-(1,1′-biphenyl)-4 propanoia acid

[0183] The operation is carried out as in Example 4, taking as startingproduct the amine hydrochloride in which R₁ represent biphenyl, insteadof the amine hydrochloride in which R₁ represent phenyl, prepared byusing as starting product the product (R)-α-[[(1,1-dimethylathoxy)carbonyl] amino][1,1′-biphenyl)-4-propanoic acid, which here is in the Rform and which is prepared as its enantiomer of S form the preparationof which is described in the following reference: Journal of MedecinalChemistry, 1995, Vol. 38, 1689, then by preparing the correspondinghydrochloride as indicated in Stage D of EP 0465369. In this way theexpected product of Example 7 is obtained.

[0184] By proceeding as in Examples 4 and 7 described above, using, ifappropriate, instead of 4′-(bromo-methyl) (1,1′-biphenyl)2-carbonitrile, 4′-2-thienyl benzyl bromide, prepared according to theprocess described in the following reference: Journal of MedicinalChemistry 38, 2357, 1995, using the 2-thienyl boronic as arylboronic, inthis way the following products of Examples 8, 9 and 10 are obtained:

EXAMPLE 8 [[[1-(mercaptomethyl)-2-biphenylethyl] amino]carbonyl]-(1,1′-thienylphenyl)-4-propanoic acid

[0185] Analyses :

[0186] MS : (M—CO₂)H+: 458

EXAMPLE 9 [[[1 (mercaptomethyl) 2-phenylethyl] amino] carbonyl](1,1-thienylphenyl) 4 propanoic acid EXAMPLE 102′-cyano-alpha-[[[1-(mercaptomethyl) 2-(paratrifluoromethylsulphonyloxy)phenylethyl] amino] carbonyl] (1,1′-biphenyl) 4-propanoic acid

[0187] Analyzes :

[0188] NMR (DMSO)

[0189] 2.6 to 3.2 (7H); 3.92 and 4.04 (m, 1H); 7.06 to 7.95 (Ar); 0.25and 0.4 (1H,NH).

EXAMPLE 11 OF PHARMACEUTICAL COMPOSITION

[0190] Tablets corresponding to the following formula were prepared;

[0191] Product of Example 4 . . . 50 mg

[0192] Excipient for a tablet completed at . . . 200 mg

[0193] (detail of excipient : lactose, talc, starch, magnesiumstearate).

PHARACOLOGICAL RESULTS

[0194] Determination of the inhibitory effect of theendothelin-converting enzyme (ECE)

[0195] A test is used, in which the product (2,2-³H)propionyl-b-ET-1(19-35) prepared as indicated below in a) is cleaved by ECE into theproduct (2,3-³H)propionyl-b-ET-1 (19-21) in the presence of product P ofwhich the inhibitory activity of ECE one wishes to determine asindicated below in b) : the inhibitory activity of ECE of the product Pwill therefore be accordingly as high as the quantity of product offormula (II) formed, determined by counting the radioactivity, will below. The operation is carried out as follows:

[0196] a)-Preparation of tritiated peptide (2,3-³H)propionyl-b-ET-1(19-25)

[0197] N-succinimidyl-(2,3-³H) -propionate (Amersham code TRK.556) is insolution in 5 ml of toluene at 1 mCi/ml, 99 mCi/mmol → 5 mCi and 50nmoles.

[0198] The toluene is evaporated off until a solution of 10 μl isobtained then 25 μl of a solution of DMSO containing 0.2 mg of b-ET-1(19-35) is added, b-ET-1 (19-35) (MW=2014.2) having previously beendried over potash overnight. Evaporation is continued for 10 minutesthen the solution is agitated under a stream of nitrogen for 15 minutesin order to eliminate the residual toluene.

[0199] Agitation is then gently carried out for 4 days.

[0200] To purify, 225 μl of phosphate buffer pH 6.5 and 50 μl ofacetonitrile are added then agitation is carried out for 10 minutes andthe radioactive solution obtained is separated into 2 injections of 150μl on a Nucleonsil C_(1Θ) column (150×4.6 mm).

[0201] Elution is carried out with a flow rate of 0.8 ml/mn with agradient of 0 to 20% of acetonitrile over 20 minutes then 20 to 35% over50 minutes.

[0202] Analyses :

[0203] Analysis of the fractions is carried out by counting the tritiumwith a liquid scintillation counter (1 μl in 5 ml of scintillatingHiSafe3) for 60 seconds.

[0204] The radioactive fractions are combined and fractionated into 200μl samples in siliconized Eppendorf tubes which can be stored at −80 °C. or −20° C.

[0205] Characteristics of the product obtained :

[0206] dpm=1 067 274 560 corresponding to 0.5 mCi.

[0207] Radioactive yield : 10%.

[0208] Specific activity: (99×10)/30.5=32.5 Ci/mmol.

[0209] b)-Determination of the inhibitory activity of the endothelinconverting enzyme (ECE)

[0210] 10 μl of ECE i.e. 1 to 2 μg of purified ECE are pre-incubated for30 minutes at 37° C., in 400 μl of a 50 mM Tris maleate buffer pH=6.5,20 μl of 5M sodium chloride and 5 μl of product P the inhibitoryactivity of which one wishes to test, in solution at differentconcentrations (comprised between 1 μM at 100 mM) (i.e. finalconcentrations in product P of 10 nM to 1 mM).

[0211] The reaction is initiated by the addition of 10 μl of(2,3-³H)propionyl-b-ET-1 (19-35) prepared as indicated above in a), at afinal concentration of 1.8.10⁻¹²M.

[0212] After incubation for one hour at 37° C., the reaction is stoppedby the addition of 600 μl of ethyl acetate and the(2,3-³H)propionyl-b-ET-1 (19-21) is extracted by mechanical agitationfor 2 minutes.

[0213] 300 μl of the organic phase is removed, 5 μl of liquidscintillator is added and the radioactivity Is counted for 1 minute witha liquid scintillation counter.

[0214] Each measurement is carried out in triplicate except for the ECEcontrol (control enzyme, without the product the ECE inhibitory activityof which one wishes to test), for which the measurement is carried outsix times.

[0215] The percentage inhibition is calculated by establishing therelationship :$\frac{{{tested}\quad {product}} - {blank}}{{{control}\quad {enzyme}} - {blank}}$

[0216] The blank is carried out starting with the solution obtainedwithout enzyme.

[0217] The test was validated by its application to known inhibitorsi.e. P1 which is phosphoramidon and P2 which isN-(phenylethylphosphonyl) -Leu-Trp (TAKEDA).

[0218] The table below gives the results obtained by using as P productsthe products in the examples in the present invention, the ECEinhibitory activities of which one wishes to test.

[0219] From the cpm's obtained and by plotting the graph of thepercentage of inhibition relative to the concentration of inhibitor(nM), the IC₅₀ is calculated which therefore corresponds to theconcentration which causes a 50% inhibition of ECE.

[0220] The numbered results obtained are indicated in the table below:

[0221] RESULTS : Products of Examples IC₅₀ (nM)  4  30  6 220 10 150

1) Use, for the preparation of medicaments intended for the treatment ofpathologies requiring an inhibition of the endothelin-converting enzyme,of the products of formula (I) :

in which : R₁ represents an phenyl or biphenyl radical optionallysubstituted by one or more radicals chosen from halogen atoms, thefollowing radicals: optionally protected hydroxyl, linear or branchedalkoxy containing up to 4 carbon atoms, cyano, free, salified,esterified or amidified carboxy, benzyloxy and the dioxol radical, n1and n2, identical or different, represent the integer 0 or 1, R₂represents a hydrogen atom or a methyl radical substituted by a phenyl,phenylthio or indolyl radical and optionally by a second phenyl radical,these phenyl, phenylthio and indolyl radicals being optionallysubstituted by one or more radicals chosen from halogen atoms, and thefollowing radicals: optionally protected hydroxyl, linear or branchedalkoxy containing up to 4 carbon atoms, cyano, free, salified,esterified or amidified carboxy, benzyloxy, thienyl, naphthyl andphenyl, these three last radicals being themselves optionallysubstituted by one or more radicals chosen from halogen atoms, thefollowing radicals: optionally protected hydroxyl, linear or branchedalkoxy containing up to 4 carbon atoms, cyano and free, salified,esterified or amidified carboxy, A represents the free, salified,esterified or amidified carboxy radical, the free or salified tetrazolylradical, or an alkyl radical, containing up to 10 carbon atoms andsubstituted by a radical chosen from the following radicals: free,salified, esterified or amidified carboxy, the optionally protectedhydroxyl, alkoxy containing up to 4 carbon atoms, phenoxy, phenyl,naphthyl, thienyl, indolyl and pyridyl, these radicals being optionallysubstituted by one or more radicals chosen from halogen atoms and thefollowing radicals: optionally protected hydroxyl, linear or branchedalkoxy containing up to 4 carbon atoms, cyano and free, salified,esterified or amidified carboxy, {circle over (1)} and {circle over (2)}indicating, if appropriate, the asymmetric centres of the products orformula (I), said products of formula (I) being in all possible racemic,enantiomeric and diastereoisomeric isomer forms, as well as the additionsalts with mineral and organic acids or with the mineral and organicbases of said products of formula (I). 2) Use as defined in claim 1, inwhich R₁, R₂, and n₂ have the meanings indicated in claim 1, n1represents the integer 1, and A represent the free, salified, esterifiedou amidified carboxy radical or an alkyl radical, containing at most 10carbon atoms and substituted by a radical chosen from the free,salified, esterified ou amidified carboxy radicals, optionally protectedhydroxyl radicals, alkoxy radical containing at most 4 carbon atoms, andphenoxy radical, said products of formula (I) being in all possibleracemic, enantiomeric and diastereoisomeric isomer forms, as well as theaddition salts with mineral and organic acids or with mineral andorganic bases of said products of formula (I). 3) Use as defined inclaim 1 or 2, in which R₁ represents a phenyl or biphenyl radical,optionally substituted by a halogen atom, or by a hydroxyl radicaloptionally in the form of of the trifluoromethylsulphonyloxy radical, n1represents the integer 1, n2 represents the integer 0, R₂ represents ahydrogen atom or a methyl radical substituted by a phenyl radical,itself optionally substituted by a thienyl or phenyl radical itselfoptionally substituted by a cyano radical, A represents the free,salified, esterified ou amidified carboxy radical or an alkyl radical,containing at most 10 carbon atoms substituted by a phenoxy radical,said products of formula (I) being in all possible racemic, enantiomericand diastereoisomeric isomer forms, as well as the addition salts orwith mineral and organic bases of said products of formula (I). 4) Useas defined in claim 1, of products the names of which follow:[S—(R^(*),S^(*))]N-[1-(mercaptomethyl)-2-phenylethyl]-alpha-[[(phenylmethoxy) carbonyl]amino]-1H-indole-3-propanamide, 2′-cyano-alpha-[[[1-(mercaptomethyl)-2-phenylethyl] amino]carbonyl](1,1′-biphenyl)-4-propanoic acid,(R)N-(1-mercaptomethyl)-2-phenylethyl)-11-phenoxy-undecanamide, saidproducts of formula (I) being in all possible racemic, enantiomeric anddiastereoisomeric isomer forms, as well as the addition salts withmineral and organic bases of said products of formula (I). 5)Preparation process for the products of formula (I) for use as definedin claim 1, characterized in that a product of formula (II);

in which n1 has the meaning indicated in claim 1 and R′₁ has the meaningindicated in claim I for R₁ in which the optional reactive functions areoptionally protected, is subjected either to the action of a compound offormula (III):

in which R′₂ has the meaning indicated in claim 1 for R₂ in which theoptional reactive functions are optionally protected, and R representsan alkyl or arylalkyl radical, in order to obtain the product of formula(IV):

in which n1, R′₁, R′₂ and R have the meanings indicated above, or to theaction of an acid halide of formula (V):

in which n2 has the meaning indicated in claim 1, Hal represents ahalogen atom, R′₂ has the meaning indicated above and A′ has the meaningindicated in claim 1 for A in which the optional reactive functions areoptionally protected, such as in particular A′ does not represent a freecarboxy radical, in order to obtain a product of formula (VI):

in which n1, n2, R′₁, R′₂ and A′ have the meanings indicated above,which products of formula (IV) and (VI), in order to obtain products offormula (I) or to convert the products of formula (I) into otherproducts of formula (I), can be treated, if desired and if necessary, toone or more or the following reactions, in any order: a saponificationreaction of the ester function into an acid function, a conversionreaction of the cyano function into an acid or tetrazolyl function, aconversion reaction of the alkoxy function into the hydroxyl function,an esterification, salification or amidification reaction of the acidfunction, a reaction which releases the thiol function from the radical

an elimination reaction of the protective groups which can be carried bythe protected reactive functions, a salification reaction by a mineralor organic acid or base in order to obtain the corresponding salt, saidproducts of formula (I) thus obtained being in all possible racemic,enantiomeric and diastereoisomeric isomer forms. 6) The followingproducts: [S—R^(*),S^(*))]N-[1-(mercaptomethyl)-2-phenylethyl]-alpha-[[(phenylmethoxy) carbonyl]amino]-1H-indole-3-propanamide, 2′-cyano-alpha-[[[1-(mercaptomethyl)-2-phenylethyl]amino]carbonyl](1,1′-biphenyl)-4-propanoic acid, (R)N-(1-mercaptomethyl)-2-phenylethyl)-11-phenoxy-undecanamide, said products being in all possible racemic,enantiomeric and diastereoisomeric isomer forms, as well as the additionsalts with pharmaceutically acceptable mineral and organic bases of saidproducts of formula (I). 7) The pharmaceutical compositions containing,as active ingredient, at least one of the products as defined in claim6. 8) Use of the products of formula (IV) and (VI) as defined in claim5, for the preparation of an inhibiting agent of theendothelin-converting enzyme. 9) Use of the products of formula (I) aAdefined in claims 1 to 4 and 8 for the preparation of pharmaceuticalcompositions intended for the treatment, by inhibition ofendothelin-converting enzyme, of illnesses such as hypertension inducedby endothlin, vascular spasms, the effects of a cerebral haemorrhage,renal insufficiencies, myocardial infarction, cardiac insufficiency, aswell as in the prevention of post-angioplasty recurrence or stenosis andcardiac and vascular fibrosis.